Oxidative Stress Enzyme May Be Central to PH Developing in COPD Patients, Study Reports

An enzyme called NOX4 appears to have a crucial role in the blood vessel remodeling that can lead to pulmonary hypertension (PH) in patients with chronic obstructive pulmonary disease (COPD), a study in China reports.

The research, “NOX4 expression and distal arteriolar remodeling correlate with pulmonary hypertension in COPD,” was published in the journal BMC Pulmonary Medicine.

People with COPD can develop PH in the lung disease’s later stages. Although more research is needed to fully unravel the mechanisms linking PH and COPD, pulmonary vascular remodeling — or alterations in the structure of blood vessels in the lungs — is regarded as a key factor in both conditions.

Some studies in COPD patients reported that an enlarged pulmonary artery correlated with cardiac dysfunction and reduced blood volume in small pulmonary vessels, but other studies had conflicting results, highlighting the complexity of this condition.

Oxidative stress — the imbalance between the production of free radicals and the body’s ability to counteract their harmful effects through antioxidants — is a major cause of COPD and is also involved in vascular remodeling, including the proliferation of cells on the vascular wall and blood vessel tightening, or vasoconstriction.

Studies show that increased levels of the NOX4 enzyme — a source of reactive oxygen species (ROS) — play a key role in the development of PH in mice. Elevated production of NOX4 was also observed in pulmonary vessels of both chronic PH and idiopathic pulmonary arterial hypertension (PAH) patients, as well as in those with COPD.

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Of note, the increase in NOX4 in COPD patients was reported to be associated with higher levels of a molecule called TGF-beta, which is implicated in inflammation, tissue remodeling, and fibrosis (scarring).

These previous findings suggest a role for NOX4 and TGF-beta in the development of PH in COPD. But how NOX4 is regulated in these patients and its clinical implications in PH-COPD needed to be explored.

Cardiac magnetic resonance imaging (cMRI) enables a thorough analysis of the heart’s structure and function, including ventricular size, wall thickness and mass, and flow velocity in blood vessels. It can be used to detect early right ventricular dysfunction and remodeling in patients whose COPD is not too severe, and to accurately diagnose PH.

Researchers here used cMRI to evaluate the structure of distal (outer) pulmonary arteries, and to analyze the link between NOX4 in these arteries and poor airflow in COPD patients. NOX 4’s potential correlation with artery remodeling, pulmonary circulation and/or ventricular structure was also explored.

They also investigated the association of NOX4 and TGF-beta in human primary artery smooth muscle cells (HPASMCs) isolated from pulmonary arteries.

Results showed a link between higher levels of NOX4 and thicker (greater volume) pulmonary vascular walls with poorer elasticity in COPD patients. The higher the volume of distal pulmonary arteries, the greater the degree of impaired pulmonary function.

Data also demonstrated that COPD patients had higher blood levels of the oxidative stress marker malondialdehyde and lower levels of superoxide dismutase, an antioxidant enzyme. Earlier studies had also reported malondialdehyde at high levels in the serum and plasma of COPD patients.

Experiments in HPASMCs indicated that TGF-beta induced the production of NOX4 and ROS, which, in turn, may cause vascular remodeling in COPD patients’ lungs.

“These results suggest that the NOX4-derived ROS production may play a key role in the development of PH in COPD by promoting distal pulmonary vascular remodeling,” the researchers wrote.